Synapse formation and elimination are critical not only to circuit development, but also to experience- dependent circuit remodeling and to maintenance of excitatory/inhibitory (E/I) balance. Dysregulation of these processes, disproportionate synapse density, and E/I imbalance are common to multiple nervous system disorders including Autism Spectrum Disorders (ASDs), Alzheimer?s Disease (AD) and Schizophrenia (SCZ). However, our understanding of the mechanisms regulating synapse density and E/I ratio is incomplete. Both excitatory and inhibitory synapses are subject to activity-dependent synaptic plasticity; patterned activity can induce synapse formation or elimination, or can produce persistent changes in structure, molecular composition, and synaptic strength. Importantly, they do not function in isolation of one another, but rather, they cooperate to maintain neuronal function and changes at one are often accompanied by changes at the other. Activity-dependent synaptic alterations are initiated by rapid posttranslational modification and subcellular redistribution of existing proteins. Such changes are supported long-term by protein synthesis, which often requires de novo mRNA synthesis. Coupling electrical activity and postsynaptic Ca2+ signaling to transcription is known as excitation-transcription (E-T) coupling: many forms of which operate downstream of L-type voltage-gated Ca2+ channels (LTCCs). One form of E-T coupling that has been well characterized by our laboratory signals via activation of the nuclear factor of activated T-cells (NFAT) family of transcription factors. LTCC Ca2+ influx activates Ca2+/calmodulin (Ca2+/CaM)-dependent protein phosphatase 2B/calcineurin (PP2B/CaN) that is localized to the channel by A-kinase-anchoring protein 79/150 (AKAP79/150), and in turn CaN dephosphorylates NFAT to promote its nuclear translocation. Evidence suggests that dysregulation of this pathway may be involved in pathological alterations to synapse density?a hypothesis that is supported by recent preliminary data from our lab. However, whether NFAT signaling regulates synapse density and E/I balance, and how this may be altered in nervous system disorders remain unclear. Thus, I propose to test the hypotheses that CaN-NFAT signaling regulates synapse density and E/I ratio and that A? can activate this pathway to alter these synaptic properties in AD?a disorder whose clinical impairment stems almost entirely from pathological synapse elimination. I will primarily use fluorescence microscopy and electrophysiology to determine the effect of enhanced CaN-NFAT signaling on excitatory and inhibitory synapse density and E/I synaptic ratio (Aim 1), and to determine if A? induces CaN- NFAT signaling and NFAT-dependent transcription to alter synapse density (Aim 2).